Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and the eight worldwide. The Pancreatic Cancer Action Network™ predicted that it will move from the 4th to the 2nd leading cause of cancer death in the US by 2020 or earlier, based on the changing demographics of the US population and changes in incidence and death rates. Pancreatic cancer has an extremely poor prognosis: for all stages combined, the 1- and 5-year relative survival rates are 25% and 6% respectively; for local disease the 5-year survival rate is approximately 15%, while the median survival for locally advanced and for metastatic disease, which collectively represent over 80% of individuals, is about 10 and 6 months respectively.
Globally, as of 2010, pancreatic cancer resulted in 310,000 deaths, up from 200,000 in 1990. In 2010, an estimated 43,000 people in the US were diagnosed with pancreatic cancer and almost 37,000 died from the disease. Pancreatic cancer has one of the highest fatality rates of all cancers, and is the fourth-highest cancer killer among both men and women worldwide. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.
Early pancreatic cancer often does not cause symptoms, and the later symptoms are usually nonspecific and varied. Therefore, pancreatic cancer is often not diagnosed until it is advanced.
Treatment of pancreatic cancer depends on the stage of the cancer. Although localized cancer is considered suitable for surgery with curative intent at present, only 20% of cases present with localized disease at diagnosis. Surgery can also be performed for palliation, if the malignancy is invading or compressing the duodenum or colon. In such cases, bypass surgery might overcome the obstruction and improve quality of life but is not intended as a cure.
In patients not suitable for resection with curative intent, palliative chemotherapy may be used to improve quality of life and gain a modest survival benefit. Gemcitabine was approved by the United States Food and Drug Administration in 1998, after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in patients with advanced pancreatic cancer. This marked the first FDA approval of a chemotherapy drug primarily for a non-survivable clinical endpoint. Yet even with this positive progress, new therapies are still needed. New nucleobase compounds with improved properties can be useful in the treatment of pancreatic cancer as well as many other indications. The compounds and methods disclosed herein address these and other needs.